Objectives:

The Vanderbilt Evidence-based Practice Center systematically reviewed evidence addressing administration of progestogens to prevent preterm birth.

Data Sources:

We searched MEDLINE^® and Embase for articles published in English from January 1966 to October 2010. A focused update was added through October 2011.

Review Methods:

We excluded publications that did not address a Key Question, were not research, or had fewer than 20 participants. We included 70 publications: 8 were good quality; 43, fair; and 19, poor. Sixteen randomized controlled trials (RCTs) contributed data for Bayesian meta-analysis. The update netted eight additional RCTs.

Results:

Among women with prior preterm birth and a singleton pregnancy (four RCTs), progestogen treatment decreased the risk of preterm birth (Odds Ratio [OR]=0.66, 95% Bayesian credible interval [BCI]: 0.53, 0.82), corresponding to an absolute reduction in risk of preterm birth between 0 and 26 percent across studies. In this population, progestogens also reduced neonatal death (OR=0.52, 95% BCI: 0.25, 0.96). Two trials of progestogen administration among women with short cervical length, one identified in the main portion of the review and the latter in the focused update, report reduction of risk of preterm birth with an absolute reduction in risk of 8.8 and 15.2 percent. Evidence of benefit for other maternal, fetal, or neonatal health outcomes is inconsistent or absent. In multiple gestations, progestogen treatment does not prevent prematurity (preterm birth OR=1.18, 95% BCI: 0.79, 1.39), enhance birthweight, or improve other outcomes.

No maternal factors, such as number or severity of prior preterm births, have been definitively shown to modify effects of progestogen treatment. Similarly, direct comparisons have not been made between routes of administration or doses in RCTs. Across RCTs (n=15), no formulation was effective at reducing risk for neonatal mortality, but all were effective at reducing the risk of preterm birth (meta-estimates: OR_17OHP¹ =0.75, 95% BCI: 0.60, 0.90 OR_Oral=0.56, 95% BCI: 0.36, 0.79; OR_Vaginal=0.76, 95% BCI: 0.57, 0.98). Evidence is insufficient to determine whether time of initiation and adherence to treatment influence outcomes. Factors associated with adherence to treatment have not been systematically studied.

Potential adverse effects (harms) were not uniformly assessed in this literature. Study participants withdrew from treatment and placebo groups in similar small proportions. Long-term maternal and infant effects have not been well studied. No data were available from large registries for surveillance of rare outcomes such as fetal death. Publications about provider- and system-level factors confirm wide variability in use of progestogens, use in populations that lack clear evidence of benefit, and desire for data about longer term benefits and risk of harms.

Conclusions:

Progestogens prevent preterm birth when used in singleton pregnancy in which the mother has had a prior spontaneous preterm birth or in which cervical length is short. The strength of the evidence supporting its use for these indications is moderate and low, respectively. In contrast, moderate strength of evidence suggests lack of effectiveness for multiple gestations. Evidence is insufficient for all other uses. Across indications, data are sparse to evaluate influence on near-term outcomes such as neonatal mortality and morbidities. Evidence is insufficient for understanding whether intervention has the ultimately desired outcome of preventing morbidity and promoting normal childhood development.